Methods and compositions for treating Raynaud&#39;s disease

ABSTRACT

In various embodiments, methods and compositions for treating Raynaud&#39;s disease and Raynaud&#39;s phenomenon are provided. Topical administration of a semisolid composition comprising a prostaglandin E1 compound provides the desired relief of the Raynaud&#39;s disease or Raynaud&#39;s phenomenon without the possible complications of systemic administration. The semisolid composition can be administered as needed, or in a regimen of several doses per day.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present invention is filed under 35 U.S.C. §371 as the U.S. nationalphase of International Application No. PCT/US2012/032577, filed Apr. 6,2012, which designated the U.S. and claims the benefit of priority toU.S. Provisional Patent Application No. 61/472,988, filed Apr. 7, 2011,which is hereby incorporated in its entirety including all tables,figures, and claims.

FIELD OF THE INVENTION

The present invention relates to methods and compositions for thetreatment of Raynaud's disease and Raynaud's phenomenon.

BACKGROUND OF THE INVENTION

Raynaud's disease (RD) and Raynaud's phenomenon (RP) are disordershaving a prevalence of about 3% to more than 5% that affect peripheralblood vessels, involving brief episodes of vasospasm causing decreasedblood flow to the fingers and toes, and rarely to the nose, ears,nipples, and lips. When this disorder occurs without any known cause, itis called Raynaud's disease, or primary Raynaud's. When the conditionoccurs along with a likely cause, it is known as Raynaud's phenomenon,or secondary Raynaud's. Raynaud's disease, most common in young women(60 to 90% of reported cases), is idiopathic. Raynaud's phenomenon issecondary to other conditions, such as connective tissue disorders,obstructive arterial diseases (arteriosclerosis obliterans,thromboangiitis obliterans, thoracic outlet syndrome), neurogeniclesions, drug intoxications (ergot, methysergide), dysproteinemias,myxedema, primary pulmonary hypertension, and trauma. Raynaud'sphenomenon is commonly found associated with certain rheumatic diseasessuch as systemic sclerosis, systemic lupus erythematosus, and rheumatoidarthritis. Secondary Raynaud's may also be a result of mechanicaltrauma, hand-arm vibration syndrome, paraprotinemias, and certainchemicals. Patients with secondary Raynaud's associated with rheumaticdiseases often have autoantibodies such as a +ANA, +anti-centromere,and/or +anti-scl-70, and visible changes in their nailfold capillarypattern. As used herein, “Raynaud's” when used without a nounencompasses both Raynaud's disease and Raynaud's phenomenon.

Cold temperatures or stressful emotions can trigger attacks of eitherprimary or secondary Raynaud's. In response to cold exposure, vasospasmin distal arteries and arterioles leads to blood being shunted from theextremities through the numerous arteriovenous anastomoses found in thedigits. In response to heat, flow is decreased through these anastamosesand instead capillary flow is increased. The classical pattern consistsof triphasic color changes of white (ischemia), blue or purple (cyanosisor deoxygenation), and red (reperfusion phase). The affected areas canthrob or feel numb and tingly. With severe Raynaud's, prolonged orrepeated episodes can cause prolonged pain, sores or tissue death(gangrene).

Since stressful emotions can trigger attacks of either primary orsecondary Raynaud's, a central nervous system component is indicated aswell as a peripheral vascular component.

There is no accepted standard method of measuring the severity of thedisease or response to therapy. The attacks of Raynaud's are difficultto elicit, and the severity of the elicited attacks varies. Since manypatients do not develop the full triphasic color changes, there is somecontroversy over proper diagnosis of the condition. In addition,complaints of sensation changes (cold, numbness, tingling, or pain) varyamong patients these changes do not strictly correlate with the observedcolor differences.

Many different classes of drugs have been used to treat patients withRaynaud's. Much work has focused on vasodilators. Calcium channelblockers are the most commonly used class of vasodilators, and have beenshown to be effective in several studies. However, many patients do notrespond or cannot tolerate these drugs because of frequent adverseeffects such as headache, flushing, and hypotension. Some studies havebeen carried out on other drugs that can improve vasodilation includingangiotensin-II type I receptor antagonist, topical nitrates, serotoninantagonists, nonselective endothelin receptor antagonist, andphosphodiesterase inhibitors.

Studies have shown that the potent vasodilators, prostaglandins andprostacyclin analogs, are beneficial for treating severe Raynaud's.Unfortunately, prostaglandins and prostacyclin analogs are typicallyadministered via intravenous infusion, necessitating hospitalization fortheir use. A few studies have examined the use of oral prostacyclinanalogs, but mixed results have been reported with one study showingbenefit, another showing no benefit over placebo. There have been only afew studies on the use of topical agents directly applied to the handsfor the treatment of Raynaud's, and while some compositions haveincluded prostanoids, most have involved nitrate compounds, such asglyceryl trinitrate, or minoxidil.

The prostacyclin analogue iloprost has been effective in secondaryRaynaud's associated with scleroderma. alprostadil has been shown to beas effective as iloprost in a blind study, and was reported to improvesevere digital ischemia associated with severe Raynaud's in anotherstudy. The prostanoids have been reported to have other effects besidesvasodilation, including decreasing endothelial injury markers, which mayimply an effect on reducing structural damage of vessel walls,decreasing neutrophil activation, inhibiting platelet aggregation, andmodulating fibrinolytic activity. These agents may therefore havelonger-term beneficial effects than that expected from their immediatevasodilatory effect. There have been reports of sustained benefit fromuse of these drugs; effects from a transdermal patch of PGE₂ werereported to last at least 84 hours, and intravenous infusions of theseagents have been reported to last from 30 days to 12 weeks.

SUMMARY OF THE INVENTION

In various embodiments, methods and compositions for treating Raynaud'sdisease and Raynaud's phenomenon are provided. Topical administration ofa semisolid composition comprising a prostaglandin E₁ compound providesthe desired relief of the Raynaud's disease or Raynaud's phenomenonwithout the possible complications of systemic administration. Thesemisolid composition can be administered as needed, or in a regimen ofseveral doses per day.

In certain embodiments, a method of treating Raynaud's disease andRaynaud's phenomenon in a subject is provided, comprising the steps ofproviding a semisolid composition comprising a prostaglandin E₁ compoundand applying an effective amount of the semisolid composition to thesurface of an affected body part. In certain embodiments, the semisolidcomposition comprises a prostaglandin E₁ compound selected from thegroup consisting of prostaglandin E₁, C₁-C₄ esters of prostaglandin E₁,and pharmaceutically acceptable salts thereof; a thickening agentselected from a polysaccharide gum, a chemically modified polysaccharidegum; a skin penetration enhancer that is selected from an N,N-di(C₁-C₈)alkylamino substituted (C₄-C₁₈) alkyl (C₂-C₁₈) carboxylic ester andpharmaceutically acceptable acid addition salts thereof; and a(C₁-C₄)-alkyl (C₈-C₂₂) carboxylic ester. In some embodiments, theN,N-di(C₁-C₈) alkylamino substituted (C₄-C₁₈) alkyl (C₂-C₁₈) carboxylicester is selected from the group consisting ofdodecyl-2-(N,N-dimethylamino)-propionate;dodecyl-2-(N,N-dimethylamino)-acetate; 1-(N,N-dimethylamino)-2-propyldodecanoate; 1-(N,N-dimethylamino)-2-propyl myristate;1-(N,N-dimethylamino)-2-propyl oleate; and pharmaceutically acceptableacid addition salts thereof. In certain embodiments, the semisolidcomposition is supplied in a unit dose dispenser. Preferably, thesemisolid composition is at room temperature when applied to the surfaceof the affected body part to avoid triggering or exacerbating thevasospasm that is characteristic of Raynaud's disease or Raynaud'sphenomenon. In certain embodiments, the semisolid composition is storedat room temperature. In some embodiments, the semisolid composition isprovided in a two-part unit dose container. In preferred embodiments,the total daily dose of a prostaglandin E₁ compound that is applied tothe surface of the affected body part is about 0.5 to about 5.7 mg. Insome embodiments the total daily dose is divided into 2-4 doses and isadministered in a regimen of separate applications over the course of12-24 hours. In a preferred embodiment, three doses are applied daily.Typically, the affected body parts are the extremities, the hands and/orthe feet. In certain embodiments, the total daily dose is applied toboth hands, or to a single hand, depending on the affected area and theseverity of the condition.

In other embodiments, a pharmaceutical composition is provided thatcomprises a prostaglandin E₁ compound for use in a treatment ofRaynaud's disease or Raynaud's phenomenon by the topical administrationof the composition to the surface of an affected body part. In certainembodiments, the pharmaceutical composition comprises a prostaglandin E₁compound selected from the group consisting of prostaglandin E₁, C₁-C₄esters of prostaglandin E₁, and pharmaceutically acceptable saltsthereof; a thickening agent selected from a polysaccharide gum, achemically modified polysaccharide gum; a skin penetration enhancer thatis selected from an N,N-di(C₁-C₈) alkylamino substituted (C₄-C₁₈) alkyl(C₂-C₁₈) carboxylic ester and pharmaceutically acceptable acid additionsalts thereof; and a (C₁-C₄)-alkyl (C₈-C₂₂) carboxylic ester. In someembodiments, the N,N-di(C₁-C₈) alkylamino substituted (C₄-C₁₈) alkyl(C₂-C₁₈) carboxylic ester is selected from the group consisting ofdodecyl-2-(N,N-dimethylamino)-propionate;dodecyl-2-(N,N-dimethylamino)-acetate; 1-(N,N-dimethylamino)-2-propyldodecanoate; 1-(N,N-dimethylamino)-2-propyl myristate;1-(N,N-dimethylamino)-2-propyl oleate; and pharmaceutically acceptableacid addition salts thereof. In certain embodiments, the pharmaceuticalcomposition is supplied in a unit dose dispenser. Preferably, thepharmaceutical composition is at room temperature when applied to thesurface of the affected body part to avoid triggering or exacerbatingthe vasospasm that is characteristic of Raynaud's disease or Raynaud'sphenomenon. In certain embodiments, the pharmaceutical composition isstored at room temperature. In some embodiments, the pharmaceuticalcomposition is provided in a two-part unit dose container. In preferredembodiments, the total daily dose of a prostaglandin E₁ compound that isapplied to the surface of the affected body part is about 0.5 to about5.7 mg. In some embodiments the total daily dose is divided into 2-4doses and is administered in a regimen of separate applications over thecourse of 12-24 hours. In a preferred embodiment, three doses areapplied daily. Typically, the affected body parts are the extremities,the hands and/or the feet. In certain embodiments, the total daily doseis applied to both hands, or to a single hand, depending on the affectedarea and the severity of the condition.

In other embodiments, the use of a prostaglandin E₁ compound for themanufacture of a semisolid pharmaceutical composition for the treatmentof Raynaud's disease or Raynaud's phenomenon is provided, wherein theRaynaud's disease or Raynaud's phenomenon is treated by the topicaladministration of the semisolid pharmaceutical composition to thesurface of an affected body part. In certain embodiments, the semisolidpharmaceutical composition comprises a prostaglandin E₁ compoundselected from the group consisting of prostaglandin E₁, C₁-C₄ esters ofprostaglandin E₁, and pharmaceutically acceptable salts thereof; athickening agent selected from a polysaccharide gum, a chemicallymodified polysaccharide gum; a skin penetration enhancer that isselected from an N,N-di(C₁-C₈) alkylamino substituted (C₄-C₁₈) alkyl(C₂-C₁₈) carboxylic ester and pharmaceutically acceptable acid additionsalts thereof; and a (C₁-C₄)-alkyl (C₈-C₂₂) carboxylic ester. In someembodiments, the N,N-di(C₁-C₈) alkylamino substituted (C₄-C₁₈) alkyl(C₂-C₁₈) carboxylic ester is selected from the group consisting ofdodecyl-2-(N,N-dimethylamino)-propionate;dodecyl-2-(N,N-dimethylamino)-acetate; 1-(N,N-dimethylamino)-2-propyldodecanoate; 1-(N,N-dimethylamino)-2-propyl myristate;1-(N,N-dimethylamino)-2-propyl oleate; and pharmaceutically acceptableacid addition salts thereof. In certain embodiments, the semisolidcomposition is supplied in a unit dose dispenser. Preferably, thesemisolid pharmaceutical composition is at room temperature when appliedto the surface of the affected body part to avoid triggering orexacerbating the vasospasm that is characteristic of Raynaud's diseaseor Raynaud's phenomenon. In certain embodiments, the semisolidpharmaceutical composition is stored at room temperature. In someembodiments, the semisolid pharmaceutical composition is provided in atwo-part unit dose container. In preferred embodiments, the total dailydose of a prostaglandin E₁ compound that is applied to the surface ofthe affected body part is about 0.5 to about 5.7 mg. In some embodimentsthe total daily dose is divided into 2-4 doses and is administered in aregimen of separate applications over the course of 12-24 hours. In apreferred embodiment, three doses are applied daily. Typically, theaffected body parts are the extremities, the hands and/or the feet. Incertain embodiments, the total daily dose is applied to both hands, orto a single hand, depending on the affected area and the severity of thecondition.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graphical representation of the results of a study of theeffects of a topical prostaglandin composition on peripheral blood flowin response to a 16° C. cold challenge in an animal model.

FIG. 2 is a graphical representation of the results of a study of theeffects of a topical prostaglandin composition on peripheral temperaturein response to a 16° C. cold challenge in an animal model.

DETAILED DESCRIPTION OF THE INVENTION

Measurement Techniques

Since the primary problem in Raynaud's is vasoconstriction of arteriesand arterioles in the digits, with shunting of blood-flow away from thedigits, various methods have been used to measure blood flow. Thesemethods include plethysmography, laser Doppler flowmetry (LDF), laserDoppler imaging (LDI), temperature measurements (direct digital andthermography), and Doppler ultrasonography. There is often significantindividual variability, with the range of values found for normalsubjects generally overlapping the range found in Raynaud's. There isalso a concern that methods such as plethysmography, laser Dopplerflowmetry, direct digital temperature reading, and Doppler ultrasoundthat require direct patient contact with the test device may disturb thepatient's circulation. Additionally, it is difficult to ensure precise,reproducible probe placement, some of these methods have the additionalissue of reproducibility if multiple readings are required from the samesubject. In contrast, LDI and thermography allow a larger area to beexamined, and do not involve direct patient contact, allowing more datato be collected, and minimizing variability related to direct patientcontact or probe placement. While the flux gradient of LDI may correlatepoorly with the temperature gradient measured by thermography, bothmethods are felt to provide useful information. Patient report measuresthat are commonly used include diaries of attacks, noting frequency,severity, trigger, and duration, and a visual analogue scale (VAS) tonote pain or severity, as well as general state of their disease.

Skin temperature, as an indirect measure of blood flow, can be affectedby both intrinsic and extrinsic factors. Thermography should be done ina temperature and humidity controlled room to minimize the effects ofthese factors on measurements. Large intra-patient variability can befound when the same patient is assayed at different times; and aninternal comparison (ratio between distal to proximal points, orcomparison between treated and placebo hands) can be used as the measureof effect.

Thermography has shown that patients with Raynaud's have a lowerbaseline skin temperature than normal subjects. Female Raynaud'spatients have also been reported to have an even lower baseline thanmales. Several treatment studies have found that a 2° C. or greaterchange in baseline temperature represents a significant change. Studieshave reported a significant increases in mean skin temperature afterintravenous administration of calcitonin gene related peptide (CGRP),PGI₂, and PGE₁, oral or sublingual nifedipine or application ofnitroglycerine tape (NTG) placement on the wrist of patients.

Several investigators have used thermography to show that recovery froma cold challenge test is abnormal in patients with Raynaud's, with a lagin the onset of rewarming, delay in the rate of recovery, and lowertemperature achieved at a set point after a cold challenge. The patternof rewarming can also be different, with normal subjects showingrewarming beginning from the finger pulps and spreading proximally,while patients with Raynaud's have rewarming beginning at the base ofthe fingers and spreading distally. A two-fold increase in rewarming wasseen 10 minutes into a CGRP, while a smaller, but still significantimprovement in rewarming was found with fluoxetine.

Laser Doppler flowmetry (LDF): and laser Doppler imaging (LDI) measuremoving particle density and flux, with flux used to represent bloodflow. The light can penetrate about 1 mm, which permits measurementsfrom superficial nutritional capillaries and deeper thermoregulatoryvessels using different wavelengths of light. LDF requires directcontact with the study target, making it difficult to compare differentsites with each other because of large variations in flux with evensmall positional changes, and significant intra individual variabilityhas been found. LDI allows the entire hand to be scanned, minimizingvariability between sites, but only a small number of studies have usedthis technique. As units reported for LDI are arbitrary, it best servesin comparison studies rather than for generating absolute standardvalues. A good correlation has been found between LDF and LDI.

LDI has been used to assess the effect of topical glyceryl trinitrate(GTN) on finger flow in comparison to petroleum jelly or no treatment. Asignificant increase in flow has been reported immediately and tenminutes after topical GTN application. A significant increase in digitalblood flow as measured by LDF has been reported after treatment withvardenafil. Application of a nitric oxide-generating cream to fingerpulps, LDF has been reported to significantly increase flux. Removal ofthe gel showed a decrease in flux, but still a significant differencebetween NO cream and placebo. Sublingual nifedipine also has beenreported to produce an increase in flux compared to placebo. IntravenousPGI₂ has been reported to cause an increase in LDF. A CGRP infusioncaused an increase LDF, along with flushing of face and hands.

Since Raynaud's attacks are typically precipitated by cold exposure,many investigators have used cold challenges to try to elicit attacks orfindings typically found in attacks. However, researchers differ intheir cold challenge methodology, with a range of temperatures used (0°C., 10° C., 12° C., 15° C., 16° C., 20° C.,) for different durations ofabout 1 to 10 minutes. Most studies use a temperature of 15 or 16° C.for 1 minute. The patient is asked to put on a thin glove that fitswell, such as a latex glove, avoiding a tight fit as well as an overlyloose fit that would trap air around the subject's hand. The hand isthen lowered into a water bath at the specified temperature for thespecified time. Some studies have specified lowering to the midmetacarpal level. After removal from the water bath, the gloves areremoved, and the study measures assayed. Temperatures and/or flow aretypically measured for 10-20 minutes after the cold challenge. There issignificant inter individual difference, but the method is felt to beuseful for therapeutic studies.

The Compositions

Suitable topical prostaglandin compositions for the practice ofpreferred embodiments of the present invention are disclosed in U.S.Pat. Nos. 6,046,244, 6,118,020, 6,323,241 and No. 6,841,574, the entirecontents of which are incorporated by reference herein.

In one preferred embodiment, the prostaglandin E composition comprisesabout 0.025 percent to about 40 percent by weight of a thickening agent(e.g., guar gum); about 0.025 percent to about 10 percent by weight of aprostaglandin E compound, preferably PGE₁ (alprostadil), or apharmaceutically acceptable salt thereof, about 0.025 to about 40percent by weight of a (C₁-C₄)-alkyl (C₈-C₂₂) carboxylic ester (e.g.,ethyl laurate), and about 0.025 percent to about 40 percent by weight ofan N,N-di(C₁-C₈) alkylamino substituted, (C₄-C₁₈) alkyl (C₂-C₁₈)carboxylic ester skin penetration enhancer (e.g., dodecyl2-(N,N-dimethylamino)-propionate or a salt thereof).

Prostaglandin E (PGE) compounds have the 9-oxo, 11α-hydroxy substituentsas well as unsaturation in the side chains. The compounds of this groupinclude prostaglandin E₁ (PGE₁) represented by the formula

prostaglandin E₂ (or PGE₂) represented by the formula

prostaglandin E₃ (or PGE₃) represented by the formula

as well as the pharmaceutically acceptable salts thereof.

PGE compounds have useful therapeutic activity as vasodilators and havebeen utilized to treat male and female sexual disorders, to controllipid metabolism, to treat ulcers, to treat inflammatory skin lesions,and the like therapeutic applications.

PGE compounds are relatively unstable, however, and tend to decompose,especially in aqueous solutions or in an aqueous environment. It has nowbeen found however, that these compounds can be effectively stabilizedin non-aqueous media that are substantially free from C₁-C₄ alcohols andinclude a (C₁-C₄)-alkyl (C₈-C₂₂) carboxylic ester, such as ethyllaurate. The PGE compositions of the invention can be combined with asuitable diluent (e.g., a buffered aqueous alcohol combination) to forma topical dosage form, such as a cream, gel, ointment, and the like,prior to use. Preferably, the ratio of thickening agent to ester is inthe range of about 0.5:1 to about 1.5:1.

The PGE compositions can be provided as a semi-solid composition in aone part dosage form, or provided as a packaged, multi-part dosage formin which an actives compartment contains the PGE composition as a unitdose and a diluent compartment contains an aqueous alcohol diluent,which when combined with the PGE composition forms a unit dose for atopical application. In the packaged, multi-part dosage forms embodyingthe present invention, the actives compartment can also contain anon-aqueous liquid bulking agent, such as a silicone oil (e.g., apolydimethylsiloxane, such as cyclomethicone USP, dimethicone USP, andthe like), a C₆-C₂₂ alcohol (e.g., benzyl alcohol or a fatty alcohol),and the like. The actives compartment, and optionally the diluentcompartment, can include a thickening agent, such as a polysaccharide(e.g., a starch, a gum, a starch derivative, or a gum derivative),polyvinylpyrrolidone, polyvinyl alcohol, a cellulose derivative (e.g.,hydroxymethyl cellulose, carboxymethyl cellulose, hydroxypropylmethylcellulose, and the like), a sugar (e.g., lactose), and the like.

The multi-part dosage form can comprise a two compartment pouch orpacket having a frangible seal between the actives compartment and thediluent compartment, such that squeezing the pouch or packet can breachthe seal and allow the contents of the two compartments to combine. Thepouch can then be manually kneaded to thoroughly mix and emulsify thecontents, affording a cream, ointment, or gel PGE topical dosage form.Alternatively, a clamp or the like can be used in lieu of a frangibleseal.

PGE₁ and PGE₂ are well known to those skilled in the art. Reference maybe had to various literature references for its pharmacologicalactivities, side effects and normal dosage ranges. See for example,Physician's Desk Reference, 51st Ed. (1997), The Merck Index, 12th Ed.,Merck & Co., N.J. (1996), and Martindale The Extra Pharmacopoeia, 28thEd., London, The Pharmaceutical Press (1982). Prostaglandin E₁ as wellas other PGE compounds referenced herein are intended to encompass alsothe pharmaceutically acceptable derivatives thereof, includingphysiologically compatible salts and ester derivatives.

Additionally, simultaneous administration of one or more non-ecosanoidvasodilators may be desirable and may in some cases exhibit asynergistic effect. The combination of prazosin with prostaglandin E₁has been found to be particularly advantageous in this regard. Suitablenon-ecosanoid vasodilators include, but are not limited to: nitratessuch as nitroglycerin, isosorbide dinitrate, erythrityl tetranitrate,amyl nitrate, sodium nitroprusside, molsidomine, linsidominechlorhydrate (“SIN-1”) and S-nitroso-N-acetyl-d,l-penicillamine(“SNAP”); amino acids such as L-arginine; long and short actingα-adrenergic blockers such as phenoxybenzamine, dibenamine,phentolamine, tamsulosin and indoramin, especially quinazolinederivatives such as alfuzosin, bunazosin, doxazosin, terazosin,prazosin, and trimazosin; vasodilative natural herbal compositions andbioactive extracts thereof, such as gosyajinki-gan, Satureja obovata,bai-hua qian-hu, lipotab, saiboku-to, vinpocetine, Gingko biloba,bacopa, Gynostemma pentaphyllum, gypenosides, Evodia rutaeacrpa,rutaecarpine, dehydroevodiamine, dan-shen, salviae miltiorrhizae radix,shosaikoto, Zizyphi fructus, ginseng and mixtures thereof (U.S. Pat. No.6,007,824); ergot alkaloids such as ergotamine and ergotamine analogs,e.g., acetergamine, brazergoline, bromerguride, cianergoline,delorgotrile, disulergine, ergonovine maleate, ergotamine tartrate,etisulergine, lergotrile, lysergide, mesulergine, metergoline,metergotamine, nicergoline, pergolide, propisergide, proterguride andterguride; antihypertensive agents such as diazoxide, hydralazine andminoxidil; vasodilators such as nimodepine, pinacidil, cyclandelate,dipyridamole and isoxsuprine; chlorpromazine; haloperidol; yohimbine;trazodone and vasoactive intestinal peptides.

The quantity of a vasoactive prostaglandin, such as prostaglandin E₁, inthe pharmaceutical composition is a therapeutically effective amount andnecessarily varies according to the desired dose, the dosage form andthe particular form of vasoactive prostaglandin used. The term“prostaglandin” as used generically herein refers to the prostaglandinfree acid and pharmaceutically acceptable derivatives thereof,including, for example prostaglandin E₁ (PGE₁), pharmaceuticallyacceptable salts and lower alkyl esters thereof (the term “lower alkyl”as used herein means straight chain or branched chain alkyl containingone to four carbon atoms). The composition generally contains between0.001 percent to 1 percent of vasoactive prostaglandin, e.g.,prostaglandin E₁, typically contains between 0.05 percent to 1 percent,preferably from 0.1 percent to 0.5 percent, based on the total weight ofthe composition.

The prostaglandin E compositions of the invention preferably areutilized to provide packaged, multi-part dosage forms in which anactives compartment contains the prostaglandin E composition as a unitdose and a diluent compartment contains an aqueous alcohol diluent,which when combined with the prostaglandin E composition forms a unitdose for a topical application. In the packaged, multi-part dosage formsembodying the present invention, the actives compartment can alsocontain a non-aqueous liquid bulking agent, such as a silicone oil(e.g., a polydimethylsiloxane, such as cyclomethicone USP, dimethiconeUSP, and the like), a C₆-C₂₂ alcohol (e.g., benzyl alcohol or a fattyalcohol), and the like. The actives compartment, and optionally thediluent compartment, can include a thickening agent, such as apolysaccharide (e.g., a starch, a gum, a starch derivative, or a gumderivative), polyvinylpyrrolidone, polyvinyl alcohol, a cellulosederivative (e.g., hydroxymethyl cellulose, carboxymethyl cellulose,hydroxypropyl methylcellulose, and the like), a sugar (e.g., lactose),and the like.

The prostaglandin E compositions of the invention preferably areutilized to provide packaged, multi-part dosage forms in which anactives compartment contains the prostaglandin E composition as a unitdose and a diluent compartment contains an aqueous alcohol diluent,which when combined with the prostaglandin E composition forms a unitdose for a topical application. In the packaged, multi-part dosage formsembodying the present invention, the actives compartment can alsocontain a non-aqueous liquid bulking agent, such as a silicone oil(e.g., a polydimethylsiloxane, such as cyclomethicone USP, dimethiconeUSP, and the like), a C₆-C₂₂ alcohol (e.g., benzyl alcohol or a fattyalcohol), and the like. The actives compartment, and optionally thediluent compartment, can include a thickening agent, such as apolysaccharide (e.g., a starch, a gum, a starch derivative, or a gumderivative), polyvinylpyrrolidone, polyvinyl alcohol, a cellulosederivative (e.g., hydroxymethyl cellulose, carboxymethyl cellulose,hydroxypropyl methylcellulose, and the like), a sugar (e.g., lactose),and the like.

The prostaglandin E compositions of the invention include a skinpenetration enhancer, which is an N,N-di(C₁-C₈) alkylamino substituted,(C₄-C₁₈) alkyl (C₂-C₁₈) carboxylic esters or pharmaceutically acceptableacid addition salts thereof. As used herein, the term “(C₄-C₁₈) alkyl(C₂-C₁₈) carboxylic ester” means an ester of a (C₄-C₁₈) alcohol and a(C₂-C₁₈) carboxylic acid. The term “N,N-di(C₁-C₈) alkylaminosubstituted,” in reference to a (C₄-C₁₈) alkyl (C₂-C₁₈) carboxylic estermeans that either the alcohol portion or the carboxylic acid portionfrom which the ester is prepared bears an amino substituent NR_(x)R_(y),wherein R_(x) and R_(y) are each independently a (C₁-C₈) alkyl group.Preferably R_(x) and R_(y) are both methyl groups.

Preferred N,N-di(C₁-C₈) alkylamino substituted, (C₄-C₁₈) alkyl (C₂-C₁₈)carboxylic esters are dodecyl-2-(N,N-dimethylamino)-propionate (DDAIP);dodecyl-2-(N,N-dimethylamino)-acetate (DDAA);1-(N,N-dimethylamino)-2-propyl dodecanoate (DAIPD);1-(N,N-dimethylamino)-2-propyl myristate (DAIPM);1-(N,N-dimethylamino)-2-propyl oleate (DAIPO); and pharmaceuticallyacceptable acid addition salts thereof. Particularly preferred is DDAIP,alone or in combination with an auxiliary permeation enhancer. DDAIP isavailable from Steroids, Ltd. (Chicago, Ill.). The preparation of DDAIPand crystalline acid addition salts thereof is described in U.S. Pat.No. 6,118,020 to Büyüktimkin, et al., which is incorporated herein byreference. Long chain similar amino substituted, alkyl carboxylic esterscan be synthesized from readily available compounds as described in U.S.Pat. No. 4,980,378 to Wong, et al., which is incorporated herein byreference. Such amino-substituted carboxylic ester penetration enhancersare also sometimes referred to as alkyl-2-(N-substitutedamino)-alkanoates and (N-substituted amino)-alkanol alkanoates. Forconvenient reference, alkyl-2-(N-substituted amino)-alkanoates and(N-substituted amino)-alkanol alkanoates can be grouped together underthe term alkyl (N-substituted amino) esters.

The penetration enhancer is present in an amount sufficient to enhancethe penetration of the prostaglandin E compound into tissue. Thespecific amount varies necessarily according to the desired release rateand specific form of prostaglandin E compound used. Generally, thisamount is in the range of about 0.01 percent to about 20 percent, basedon the total weight of a topical dosage is prepared by mixing aprostaglandin E composition of the invention and an aqueous alcoholicdiluent, as described herein.

Natural and modified polysaccharides (e.g., gums) can be utilized as aviscosity enhancing agent for the prostaglandin E composition. Suchthickening agent can optionally be present in the diluent or in both theprostaglandin E composition and the diluent. Suitable representativegums are the natural and modified galactomannan gums. A galactomannangum is a carbohydrate polymer containing D-galactose and D-mannoseunits, or other derivatives of such a polymer. There is a relativelylarge number of galactomannans, which vary in composition depending ontheir origin. The galactomannan gum is characterized by a linearstructure of β-D-mannopyranosyl units linked (1->4). Single memberedα-D-mannopyranosyl units, linked (1->6) with the main chain, are presentas side branches. Galactomannan gums include guar gum, which is thepulverized endosperm of the seed of either of two leguminous plants(Cyamposis tetragonalobus and psoraloids) and locust bean gum, which isfound in the endosperm of the seeds of the carob tree (Ceratoniasiliqua). Suitable modified polysaccharide gums include ethers ofnatural or substituted polysaccharide gums, such as carboxylmethylethers, ethylene glycol ethers and propylene glycol ethers.

Other suitable representative gums include agar gum, carrageenan gum,ghatti gum, karaya gum, rhamsan gum and xanthan gum. The composition ofthe present invention may contain a mixture of various gums, or mixtureof gums and acidic polymers.

Gums, and galactomannan gums in particular, are well-known materials.See for instance, Industrial Gums: Polysaccharides & Their Derivatives,Whistler R. L. and BeMiller J. N. (eds.), 3^(rd) Ed. Academic Press(1992) and Davidson R. L., Handbook of Water-Soluble Gums and Resin,McGraw-Hill, Inc., N.Y. (1980). Most gums are commercially available invarious forms, commonly a powder, and ready for use in food and topicalcompositions. For example, locust bean gum in powdered form is availablefrom Tic Gums Inc. (Belcam, Md.).

Thickening agents preferably are present in the range of about 0.025 toabout 40 percent by weight in the prostaglandin E compositions of theinvention, and about 0.1 percent to about 5 percent by weight, based onthe total weight of a topical dosage form prepared by mixing aprostaglandin E composition and diluent. The preferred range ofthickening agent present in the topical dosage form is about 0.5 percentto 3 percent.

Alternative thickening agents include cross-linked polyacrylic acidpolymers and cellulose derivatives (e.g., carboxymethyl cellulose,hydroxymethyl cellulose, hydroxypropyl methyl cellulose, and the like).

A common variety of polyacrylic acid polymer is known generically as“carbomer.” Carbomer is polyacrylic acid polymers lightly cross-linkedwith polyalkenyl polyether. It is commercially available from the B. F.Goodrich Company (Akron, Ohio) under the designation “CARBOPOL®.” Aparticularly preferred variety of carbomer is that designated as“CARBOPOL® 940.”

Other polyacrylic acid polymers suitable for use are those commerciallyavailable under the designation “PEMULEN™” (B.F. Goodrich Company) and“POLYCARBOPHIL™” (A.H. Robbins, Richmond, Va.). The PEMULEN™ polymersare copolymers of C₁₀ to C₃₀ alkyl acrylates and one or more monomers ofacrylic acid, methacrylic acid or one of their simple esterscross-linked with an allyl ether of sucrose or an allyl ether ofpentaerythritol. The POLYCARBOPHIL™ product is polyacrylic acidcross-linked with divinyl glycol. Where polyacrylic acid polymers arepresent, they represent about 0.5 percent to about 5 percent of thecomposition, based on its total weight.

The concentration of (C₁-C₄)-alkyl (C₈-C₂₂) carboxylic ester (e.g.,ethyl laurate, isopropyl myristate, isopropyl laurate, or a mixture oftwo or more thereof) in the prostaglandin E compositions of theinvention necessarily varies according to various factors such as thedesired semi-solid consistency and the desired skin penetrationpromoting effects. Suitably, the concentration of (C₁-C₄)-alkyl (C₈-C₂₂)carboxylic ester is the range of about 0.025 percent to about 40 percentby weight based on the total weight of the prostaglandin E composition.The preferred composition contains a (C₁-C₄)-alkyl (C₈-C₂₂) carboxylicester in the range of about 0.5 percent to about 35 percent by weightbased on the total weight of the prostaglandin E composition.

An optional, but preferred, component is an emulsifier, which can bepresent in the prostaglandin E composition or in the diluent. A suitableemulsifier generally exhibits a hydrophilic-lipophilic balance numbergreater than 10. Sucrose esters, and specifically sucrose stearate, canserve as emulsifiers for the composition. Sucrose stearate is awell-known emulsifier available from various commercial sources. When anemulsifier is used, sucrose stearate, present in an amount up to about 2percent, based on the total weight of the composition, is preferred. Thepreferred amount of sucrose stearate emulsifier can also be expressed asa weight ratio of emulsifier to polysaccharide gum.

Other suitable emulsifiers are the polyoxyethylene sorbitan esters, longchain alcohols, preferably cetostearyl alcohol, and fatty acidglycerides. Suitable polyoxyethylene sorbitan esters include themonolaurate (TWEEN® 20, SPAN® 20) the monopalmitate (TWEEN® 40), themonostearate (TWEEN® 60), and the monooleate (TWEEN® 80) and mixturesthereof. Preferred fatty acid glycerides include glyceryl monooleate,triolein, trimyristin and tristearin.

Another optional ingredient is an antifoam agent, a chemical thatreduces the tendency of the finished preparation to generate foam onshaking or agitation. Silicones are the preferred antifoam agents;however, a wide variety of alcohols and lipids exhibit similarproperties. With the exception of alcohols, the selected antifoam agentmust be effective in relatively small concentrations, and are employedin trace amounts. Illustrative antifoam agents are dimethicone, cetyldimethicone, dimethicone silylate, dimethiconol, a mixture ofdimethicone and hydrated silica, isopropyl alcohol, hexyl alcohol,trimethylsiloxysilicate, triphenyl trimethicone and the like. Aparticularly preferred antifoam agent is a mixture of dimethicone withan average chain length of 200 to 300 dimethylsiloxane units andhydrated silica, commercially available under the designationSIMETHICONE® USP from Dow Corning Corporation, Michigan.

The prostaglandin E compositions of the invention are substantially freefrom C₁-C₄ alcohols (e.g., methanol, ethanol, and the like). It has beenfound that lower alkyl alcohols, such as ethanol, can lead todegradation of prostaglandin E compounds during storage for prolongedperiods of time (e.g., weeks to months). As used herein, the phrase“substantially free from C₁-C₄ alcohols” means that the compositions donot contain a destabilizing amount of lower alkyl alcohols. Preferably,the compositions contain not more than trace levels of lower alkylalcohols, which may be present as a byproduct or contaminant from one ormore of the components of the prostaglandin E composition (e.g., traceethanol from ethyl laurate). Typically, the prostaglandin E compositionsof the invention include not more than about 0.5 percent by weight ofC₁-C₄ alcohols prior to mixing with a diluent.

Aqueous alcoholic diluents useful for mixing with the prostaglandin Ecompositions of the invention can include one or more buffering agents(i.e., buffer systems), if desired. Buffer systems are chosen tomaintain or buffer the pH of compositions within a desired range. Theterm “buffer system” or “buffer” as used herein refers to a solute agentor agents which, when in a water solution, stabilize such solutionagainst a major change in pH (or hydrogen ion concentration or activity)when acids or bases are added thereto. Solute agent or agents, which arethus responsible for a resistance or change in pH from a startingbuffered pH value in the range indicated above are well known. Whilethere are countless suitable buffers, potassium phosphate buffers (e.g.,potassium phosphate monohydrate, KH₂PO₄ N.F., and the like) have proveneffective for compositions of the present invention and are preferred.

The final pH value of the topical composition prepared by thecombination of prostaglandin E composition and diluent may vary withinthe physiological compatible range. Necessarily, the final pH value isone not irritating to human skin and preferably such that transdermaltransport of the prostaglandin E compound is facilitated. Withoutviolating this constraint, the pH may be selected to improveprostaglandin E compound stability and to adjust consistency whenrequired. In one embodiment, the preferred pH value is about 3.0 toabout 7.4, more preferably about 3.0 to about 6.5, most preferably fromabout 3.5 to about 6.0.

Preferably, the water present in the diluent is purified, e.g.,deionized water. The diluent preferably contains water in the range ofmore than about 5 to about 95 percent by weight based on the totalweight of the diluent. The specific amount of water present is notcritical, however, being adjustable to obtain the desired viscosity(usually about 50 cps to about 30,000 cps) and/or concentration of thecombination when mixed with the prostaglandin E composition. The topicalcomposition formed by mixing the prostaglandin E composition and diluentpreferably has a viscosity of at least about 30 centipoise. Viscosityenhancing agents can be included to afford the desired level ofviscosity. The diluent also preferably includes up to about 95 percentby weight of a C₁-C₄ alcohol (e.g., ethanol).

Prostaglandin E compound stabilizers and excipients, such as organicacids and alcohols, cyclodextrins, coloring agents, rheological agents,and preservatives can be added to the extent that they do not limit thestability or penetration of the prostaglandin E compound.

The ingredients listed above may be combined in any order and mannerthat produces a composition for ultimately receiving the prostaglandin Ecompound, such as prostaglandin E₁ and the like, preferablysubstantially evenly dispersed throughout. Methods of mixing andcompounding pharmaceutical compositions, such as the prostaglandin Ecompositions of the invention, are well known in the art.

A preferred diluent for use in a two-part packaged dosage form of theinvention comprises 1 to about 20 percent by weight ethanol, 80 to 99percent by weight water, and a suitable amount of one or more bufferingagent to maintain a desired physiologically compatible pH in a topicaldosage form prepared by combining the prostaglandin E composition anddiluent.

Variations in the treating compositions which do not adversely affectthe effectiveness of the prostaglandin E compound would be evident toone skilled in the art, and are within the scope of this invention. Forexample, additional ingredients such as coloring agents, anti-microbialpreservatives, emulsifiers, lubricants, perfumes, prostaglandin Ecompound stabilizers, and the like, may be included as long as theresulting preparation retains desirable properties, as described above.When present, preservatives are usually added in amounts of about 0.05to about 0.30%. Suitable preservatives include methylparabens (methylPABA), propylparabens (propyl PABA) and butylhydroxy toluene (BHT). Afragrance can be included in the composition in an amount up to about 5percent by weight, based on the total weight of the composition.Suitable perfumes and fragrances are known in the art. A non-limitingexample of a suitable fragrance is myrtenol, preferably utilized in anamount of up to about 2 percent by weight.

The compositions of the present invention can also include a smallamount (e.g., about 0.01 to about 4 percent by weight) of a topicalanesthetic, if desired. Typical topical anesthetics include lidocaine,benzocaine, dyclonine, dibucaine, pharmaceutically acceptable salts andmixtures thereof. In one preferred embodiment, the topical anesthetic isabout 0.5 percent dyclonine, based on the weight of the composition.

An illustrative two-component dosage form is set forth in Table 1,below:

TABLE 1 Amount, parts by weight More Preferred Preferred Activescompartment A prostaglandin E compound such as PGE₁ 0.025-10 0.5-5  Askin penetration enhancer (e.g., dodecyl 0.025-40 0.4-352-(N,N-dimethylamino)-propionate•HCl) A (C₁-C₄)-alkyl (C₈-C₂₂)carboxylic ester 0.025-40 0.5-35 (e.g., ethyl laurate) A viscosityenhancer (e.g., guar gum) 0.025-40 0.5-35 Diluent compartment Water(deionized or U.S.P.)    5-95  40-95 Ethanol    1-75   3-40 Phosphatebuffer (pH 5.5) Q.S.

If desired, preservatives such as methyl paraben, propyl paraben,benzalkonium chloride, benzethonium chloride, and the like, can beincluded in the PGE composition and/or the diluent, as well. Theprostaglandin E composition and diluent can be combined with agitationto form a topical prostaglandin E dosage form.

In another embodiment, compounds of prostaglandin E group are stabilizedas non-aqueous compositions that include the compound together with abulking agent that can be a non-aqueous liquid, or a solid in sheet,film, or powder form. Optionally, a skin penetration enhancer can bepresent. Suitable such compositions are disclosed in U.S. Pat. No.6,841,574, which is incorporated herein by reference. Such a preferrednon-aqueous, solid dosage form comprises a compound of prostaglandin Egroup substantially uniformly distributed in a carrier sheet or film. Apredetermined size portion of this sheet or film can be applied to thesurface of a moistened body part or introduced directly into a moistbody cavity to release the prostaglandin compound. Alternatively apredetermined size portion of the sheet or film that includes aprostaglandin compound can be dissolved in an aqueous or non-aqueoussolvent that serves as a physiologically compatible delivery vehicle forthe prostaglandin compound. For topical applications, the topicaldelivery vehicle is viscous and substantially non-flowing, such as acream, gel, or ointment.

Prostaglandin E compounds can be incorporated as substantially uniformlydistributed solids in a sheet-form material, i.e., sheet or film, of aphysiologically compatible polymeric material, e.g., a cellulosic ethersuch as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and thelike, a polysaccharide such as starch, polyvinylpyrrolidone, and thelike. Sheet-form materials having a thickness of no more than about 10mils are commonly referred to as films, and those having a thickness ofmore than about 10 mils are commonly referred to as sheets. The term“sheet-form” as used herein and in the appended claims refers to sheetsas well as films. The sheet-form material can be a solid or a porousmaterial, e.g., a sponge or the like. The sheet-form material containinga prostaglandin E compound dispersed therein can be converted intodiscs, tablets, pellets, and the like, if desired.

These sheet-form articles of manufacture can be water soluble for directintroduction into moist body cavities or soluble in a non-aqueousphysiologically compatible solvent for the preparation of a cream orointment suitable for topical application. The water soluble moiety ofthe prostaglandin-bearing sheet-form material can also be utilized, ofcourse, for the preparation of aqueous gels based on a polycarbophil, apolyoxyethylene-polyoxypropylene block copolymer, e.g., the so-calledpoloxamers, and on mixtures thereof, as well as non-aqueous gels basedon the polysorbates, liquid block copolymers of propylene oxide andethylene oxide, and the like.

If desired, the prostaglandin E compound-bearing sheet form materials ofthe present invention can also include physiologically compatibleplasticizers, solubility enhancers (e.g.,hydroxypropyl-beta-cyclodextrin), and the like.

These prostaglandin E-bearing sheet-form materials can be prepared byfirst forming a solution of the desired prostaglandin E compound in anon-aqueous solvent such as a C₂ to C₄ aliphatic alcohol, e.g.,methanol, ethanol, propanol, isopropanol, n-butanol and the like,together with the polymeric material, with or without a skin penetrationenhancer, then casting the solution continuously on a roll or batchwisein a shallow dish or pan, and thereafter evaporating the solventtherefrom. The resulting sheet or film has the prostaglandin E compoundsubstantially uniformly distributed throughout in an non-aqueous mediumthat can be readily subdivided and apportioned into desired unit doseseach having a predetermined PGE content. The cast sheet or film can alsobe retained on a solid surface for storage and dissolved immediatelyprior to use.

In other embodiments, the prostaglandin E compound is incorporated in atransdermal patch. Suitable transdermal patches are disclosed, forexample in U.S. Pat. No. 5,480,648 and U.S. Pat. No. 7,087,240.

The foregoing unit doses can be utilized to provide packaged, pairedcompartment dosage forms in which an actives compartment contains theprostaglandin E compound unit dose and an inerts compartment containsthe delivery vehicle for a topical application. In the packaged,paired-compartment dosage forms embodying the present invention, theactives compartment can also contain the prostaglandin E compoundtogether with a bulking agent in a non-aqueous liquid, particulate orgranular form. Suitable liquid bulking agents are silicone oils such asthe polydimethylsiloxanes, e.g., cyclomethicone USP, dimethicone USP,and the like. Suitable solid bulking agents for this particular purposeare the cyclodextrins such as hydroxypropyl-beta-cyclodextrin, betacyclodextrin, gamma cyclodextrin, and the like, the polysaccharides suchas starches, gums, and the like polyvinylpyrrolidone, polyvinyl alcohol,the methyl celluloses, sugars, and the like.

A particularly preferred present solid dosage form comprises at leastone PGE compound, preferably PGE₁, and an alkyl (N-substituted amino)ester, both substantially uniformly distributed in the carrier sheet oradmixed with one another in an actives compartment of a packagedpaired-compartment dosage form. PGE₁ and PGE₂ are particularly preferredvasoactive agents for the present purposes.

Among the suitable penetration enhancers for use in the present soliddosage forms dodecyl 2-(N,N-dimethylamino)-propionate and crystallinesalts thereof are generally preferred. The preparation of suchcrystalline salts is described in U.S. Pat. No. 6,118,020 to Büyüktimkinet al.

The penetration enhancer is present in an amount sufficient to enhancethe penetration of the prostaglandin E compound into tissue. Thespecific amount varies necessarily according to the desired release rateand specific form of prostaglandin E compound used. Generally, thisamount is in the range of about 0.01 percent to about 20 percent, basedon the total weight of the composition.

The desired release rate, including controlled or sustained release ofthe active compound can also be modulated by selection of the topicaldelivery vehicle, e.g., a hydrophobic vehicle such aspolydimethylsiloxanes and the like. Carboxy-terminatedpolydimethylsiloxanes can also enhance skin permeation by the activecompound.

Natural and modified polysaccharide gums can also be present as part ofthe carrier sheet or the topical delivery vehicle. Suitablerepresentative gums are the natural and modified galactomannan gums, asdescribed above. Suitable modified polysaccharide gums include ethers ofnatural or substituted polysaccharide gums, such as carboxylmethylethers, ethylene glycol ethers and propylene glycol ethers.

When present, the polysaccharide gums are present in the range of about0.1 percent to about 5 percent, based on the total weight of thecomposition, with the preferred range being in the range of about 0.5percent to 3 percent. In one preferred embodiment, about 2.5 percent byweight of a polysaccharide gum is present. An optional alternative tothe polysaccharide gum is a polyacrylic acid polymer, as describedabove.

The concentration of lipophilic compound required necessarily variesaccording to other factors such as the desired semi-solid consistencyand the desired skin penetration promoting effects. Suitably theconcentration of lipophilic compound is the range of about 0.5 percentto about 40 percent by weight based on the total weight of thecomposition. The preferred topical composition contains lipophiliccompound in the range of about 7 percent to about 40 percent by weightbased on the total weight of the composition.

Where a mixture of aliphatic alcohol and aliphatic ester are employed,the suitable amount of alcohol is in the range of about 0.5 percent toabout 75 percent. In one preferred embodiment, the amount of alcohol isin the range of about 5 percent to about 15 percent, while that ofaliphatic ester is in the range of about 2 percent to about 15 percent(again based on the total weight of the composition). In anotherpreferred embodiment, the amount of alcohol is in the range of about 0.5percent to about 10 percent, while that of aliphatic ester is in therange from zero percent to about 10 percent (again based on the totalweight of the composition).

An optional, but preferred, component is an emulsifier. A suitableemulsifier generally exhibits a hydrophilic-lipophilic balance numbergreater than 10. Sucrose esters, and specifically sucrose stearate, canserve as emulsifiers for the composition. Sucrose stearate is awell-known emulsifier available from various commercial sources. When anemulsifier is used, sucrose stearate, present in an amount up to about 2percent, based on the total weight of the composition, is preferred. Thepreferred amount of sucrose stearate emulsifier can also be expressed asa weight ratio of emulsifier to polysaccharide gum.

Other suitable emulsifiers are the polyoxyethylene sorbitan esters, longchain alcohols, preferably cetostearyl alcohol, and fatty acidglycerides. Suitable polyoxyethylene sorbitan esters include themonolaurate (TWEEN® 20, Span 20) the monopalmitate (TWEEN® 40), themonostearate (TWEEN® 60), and the monooleate (TWEEN® 80) and mixturesthereof. Preferred fatty acid glycerides include glyceryl monooleate,triolein, trimyristin and tristearin. Another optional ingredient is anantifoam agent, a chemical that reduces the tendency of the finishedpreparation to generate foam on shaking or agitation.

The composition can include a buffer system, if desired. Buffer systemsare chosen to maintain or buffer the pH of compositions within a desiredrange. The term “buffer system” or “buffer” as used herein refers to asolute agent or agents which, when in a water solution, stabilize suchsolution against a major change in pH (or hydrogen ion concentration oractivity) when acids or bases are added thereto. Solute agent or agentswhich are thus responsible for a resistance or change in pH from astarting buffered pH value in the range indicated above are well known.While there are countless suitable buffers, potassium phosphatemonohydrate has proven effective for compositions of the presentinvention and is preferred.

The final pH value of the pharmaceutical composition may vary within thephysiological compatible range. Necessarily, the final pH value is onenot irritating to human skin and preferably such that transdermaltransport of the prostaglandin E compound is facilitated. Withoutviolating this constraint, the pH may be selected to improveprostaglandin E compound stability and to adjust consistency whenrequired. In one embodiment, the preferred pH value is about 3.0 toabout 7.4, more preferably about 3.0 to about 6.5, most preferably fromabout 3.5 to about 6.0.

For preferred topical delivery vehicles the remaining component of thecomposition is water, which is necessarily purified, e.g., deionizedwater. Such delivery vehicle compositions contain water in the range ofmore than about 50 to about 95 percent, based on the total weight of thecomposition. The specific amount of water present is not critical,however, being adjustable to obtain the desired viscosity (usually about50 cps to about 10,000 cps) and/or concentration of the othercomponents. The topical delivery vehicle preferably has a viscosity ofat least about 30 centipoises.

Prostaglandin E compound stabilizers such as organic acids and alcohols,cyclodextrins, coloring agents, rheological agents, and preservativescan be added to the extent that they do not limit penetration of theprostaglandin E compound.

The ingredients listed above may be combined in any order and mannerthat produces a composition for ultimately receiving the prostaglandin Ecompound, such as PGE₁ and the like, preferably substantially evenlydispersed throughout. One available approach to preparing suchcompositions involves evenly dispersing the polysaccharide gum (orpolyacrylic acid) in a premixed water/buffer solution and thenthoroughly homogenizing (i.e., mixing) the resulting mixture. Whenpresent, the emulsifier is added to the water/buffer solution beforeaspersing the polysaccharide gum. Any suitable method of adjusting pHvalue to the desired level may be used, for example, by addingconcentrated phosphoric acid or sodium hydroxide.

The prostaglandin E compound, with or without a penetration enhancer, isthen combined therewith prior to use with mixing.

In one embodiment, a preparation ready for application comprises about0.01 percent to about 5 percent modified polysaccharide gum; about 0.001percent to about 1 percent of a prostaglandin E compound, preferablyPGE₁, or a pharmaceutically acceptable salt thereof, a lower alkyl esterthereof and mixtures thereof; about 0.5 percent to about 10 percentdodecyl 2-(N,N-dimethylamino)-propionate or a salt thereof; about 0.5percent to about 10 percent of a lower alcohol selected from the groupconsisting of ethanol, propanol, isopropanol and mixtures thereof; about0.5 percent to about 10 percent on an ester selected from the groupconsisting of ethyl laurate, isopropyl myristate, isopropyl laurate andmixture thereof; based on the weight of the preparation, together withan acid buffer. Preferably the preparation also comprises up to about 2percent by weight sucrose stearate.

Variations in the treating compositions which do not adversely affectthe effectiveness of the prostaglandin E compound would be evident toone skilled in the art, and are within the scope of this invention. Forexample, additional ingredients such as coloring agents, anti-microbialpreservatives, emulsifiers, lubricants, perfumes, prostaglandin Ecompound stabilizers, and the like, may be included as long as theresulting preparation retains desirable properties, as described above.When present, preservatives are usually added in amounts of about 0.05to about 0.30%. Suitable preservatives include methylparabens (methylPABA), propylparabens (propyl PABA) and butylhydroxy toluene (BHT).Suitable perfumes and fragrances are known in the art; a suitablefragrance is up to about 5 percent and fragrances are known in the art;a suitable fragrance is up to about 5 percent myrtenol, preferably about2 percent myrtenol, based on the total weight of the composition. Thecompositions of the present invention can also include a small amount,about 0.01 to about 4 percent by weight, of a topical anesthetic, ifdesired. Typical topical anesthetics include lidocaine, benzocaine,dyclonine, dibucaine, pharmaceutically acceptable salts and mixturesthereof. In one preferred embodiment, the topical anesthetic is about0.5 percent dyclonine, based on the weight of the composition.

EXAMPLE 1

A placebo controlled study was performed in an animal model of Raynaud'sdisease to examine the effect of application of a topical prostaglandinE₁ composition in response to a 16° C. cold challenge. The resultsshowed that topical application of a composition containing 0.22 weightpercent prostaglandin E₁ produced a substantial increase in blood flow.

TABLE 2 Weight percent Ingredient Test Placebo alprostadil, USP 0.22 —Guar gum (Jaguar HP-120, 2.5 2.5 Rhodia) DDAIP HCl 2.5 2.5 Ethanol,anhydrous 5.0 5.0 Ethyl laurate, FCC, Penta 3.0 3.0 Potassium phosphate,monobasic qs pH qs pH Phosphoric acid qs pH qs pH Sodium hydroxide qs pHqs pH Purified water qs qs

Female hairless rats (about 250 g, Harlan Laboratories, Inc.,Indianapolis, Ind.) were used for the test and placebo groups (ten ratsper group). The test and placebo compositions having the ingredientslist in Table 2, above, were prepared and stored at 4° C. The rats wereplaced in restraint, and test composition or placebo composition thathad been allowed to come to room temperature was applied to the entiretail of each rat 10 minutes before the cold challenge, the test groupreceiving the test composition at a dose of 220 μg of alprostadil, andthe control group receiving the placebo composition. The cold challengewas performed by submerging the tails into a 16° C. cold water bath.

Blood flow and temperature of the skin at the base of the tail weremeasured using a laser Doppler flowmeter and an infrared thermometer atthe following times: before application of the cream (t minus 10minutes), 10 minutes after the application of the cream (immediatelybefore the start of the cold challenge at t₀), and at 30, 60, and 90minutes after the start of the 16° C. (60.8° F.) cold challenge. Whenmaking the measurements, the tail was removed from the water bath andwiped dry before the blood flow and temperature were measured. The tailswere replaced in the water bath immediately after the measurements weremade.

The results of the study are presented in FIG. 1 and FIG. 2. FIG. 1 is agraphical representation of the results of a study of the effects of atopical prostaglandin composition on peripheral blood flow in responseto a 16° C. cold challenge. The mean tail blood flow (as ElectricFlux=V*m) and the standard error of the mean are plotted against timefor treatment with the test alprostadil composition (filed triangles)and the placebo composition (filled squares). A significant increase inblood flow is seen in the alprostadil treated group that peaks at 60minutes. FIG. 2 is a graphical representation of the results of a studyof the effects of a topical prostaglandin composition on peripheraltemperature in response to a 16° C. (60.8° F.) cold challenge. Both testand placebo groups showed a similar reduction in tail temperature thatapproached that of the water bath when the animals treated with thealprostadil composition produced a substantial increase in blood flowcompared to the control group (compare FIG. 1 and FIG. 2 at 30, 60 and90 minutes).

EXAMPLE 2

A randomized, placebo (vehicle) controlled, double blind cross-overdesigned dose ranging study trial is performed to assess the efficacyand tolerability of alprostadil alprostadil for Raynaud's phenomenonsecondary to systemic sclerosis he ability of a test compound toincrease blood flow in the fingers of study subjects

Objectives:

The primary objective is to decrease a Composite Index for Raynaud'sPhenomenon (including Raynaud's Condition Score (RCS), patient globalassessment, physician global assessment, attack frequency, attackduration and attack Symptom. Score (pain, numbness and tingling) inpatients with Raynaud's phenomenon secondary to systemic sclerosisfollowing treatment with topical alprostadil across a range of doses for4 week in-life period and to determine the optimal dose for clinicalusage.

Secondary objectives include assessments of tolerability as well asother clinical measures of quality of life and subject functional statusas well as pilot information regarding clinical effects on healing andprevention of digital tip ischemic ulceration.

Substudies include assay of 15-keto-PG after both acute and chronicdosing (pharmacokinetics) as well as laser Doppler velocimetry studiesof digital perfusion during cold challenge to clarify physiologiceffects (pharmacodynamics).

Study Design:

This is a phase 3 multicenter, prospective, randomized, double-blind,within-cohort crossover design study of topical alprostadil in subjectswith Raynaud's Phenomenon secondary to systemic sclerosis. The subjects,Principal Investigator (PI), clinical staff and medical monitor remainblinded to study drug administration. Eligible subjects who provideinformed consent are randomized to one of three treatment groups:

-   -   Group 1: Placebo run-in; alprostadil topical cream, 0.33% w/w in        50 mg of cream (165 μg alprostadil) or placebo applied to each        hand three times daily; wash-out; placebo or alprostadil topical        cream, 0.33% w/w in 50 mg of cream (165 μg alprostadil) applied        to each hand three times daily, resulting in a total dose of 990        μg alprostadil applied daily.    -   Group 2: Placebo run-in; alprostadil topical cream, 0.42% w/w in        112.5 mg of cream (472.5 μg alprostadil) or placebo applied to        each hand three times daily; wash-out; placebo or alprostadil        topical cream, 0.42% w/w in 112.5 mg of cream (472.5 μg        alprostadil) applied to each hand three times daily, resulting        in a total dose of 2835 μg alprostadil applied daily    -   Group 3: Placebo run-in; alprostadil topical cream, 0.42% w/w in        225 mg of cream (945 μg alprostadil) or placebo applied to each        hand three times daily; wash-out; placebo or alprostadil topical        cream, 0.42% w/w in 225 mg of cream (945 μg alprostadil) applied        to each hand three times daily, resulting in a total dose of        5670 μg alprostadil applied daily

The order of treatments, placebo vs active study drug, is randomized.

Subjects are observed for one week prior to receiving placebo (vehiclecream). After two weeks of self-administration of topical placebo cream(vehicle), subjects self-administer topical active study drug or placeboat their assigned dose. After four weeks of active treatment, subjectshave a two week wash-out period. Following the wash-out period, subjectscross-over to the other treatment (placebo or assigned dose of activestudy drug) for four weeks. Subjects then cease therapy and are followedfor two weeks (refer to Table 3). The Schedule of Assessments ispresented in Table 4, below.

TABLE 3 Study Design LEAD-IN CYCLE (all subjects) Day −21* Day −20 Day−19 Day −18 Day −17 Day −16 Day −15 No Treatment No Treatment NoTreatment No Treatment No Treatment No Treatment No Treatment Day −14*Day −13 Day −12 Day −11 Day −10 Day −9 Day −8 Placebo Placebo PlaceboPlacebo Placebo Placebo Placebo Day −7 Day −6 Day −5 Day −4 Day −3 Day−2 Day −1 Placebo Placebo Placebo Placebo Placebo Placebo PlaceboPlacebo-responders 

 withdrawn from study Placebo non-responders 

 randomized to one of three dose levels: Group 1 Group 2 Group 3TREATMENT CYCLE 1 Days 1 to 28¹ Days 1 to 28¹ Days 1 to 28¹ Active orplacebo Active or placebo Active or placebo WASHOUT CYCLE Days 29 to 42¹Days 29 to 42¹ Days 29 to 42¹ No Study Drug No Study Drug No Study DrugTreatment Crossover TREATMENT CYCLE 2 Days 43 to 70¹ Days 43 to 70¹ Days43 to 70¹ Active or placebo Active or placebo Active or placebo LEAD-OUTCYCLE Days 71 to 84¹ Days 71 to 84¹ Days 71 to 84¹ No Study Drug NoStudy Drug No Study Drug *Clinic visit ¹The last day of each cycle is aclinic visit Group 1: Placebo run-in; alprostadil topical cream, 0.33%w/w in 50 mg of cream (165 μg alprostadil) or placebo applied to eachhand three times daily; wash-out; placebo or alprostadil topical cream,0.33% w/w in 50 mg of cream (165 μg alprostadil) applied to each handthree times daily, resulting in a total dose of 990 μg alprostadilapplied daily. Group 2: Placebo run-in; alprostadil topical cream, 0.42%w/w in 112.5 mg of cream (472.5 μg alprostadil) or placebo applied toeach hand three times daily; wash-out; placebo or alprostadil topicalcream, 0.42% w/w in 112.5 mg of cream (472.5 μg alprostadil) applied toeach hand three times daily, resulting in a total dose of 2835 μgalprostadil applied daily Group 3: Placebo run-in; alprostadil topicalcream, 0.42% w/w in 225 mg of cream (945 μg alprostadil) or placeboapplied to each hand three times daily; wash-out; placebo or alprostadiltopical cream, 0.42% w/w in 225 mg of cream (945 μg alprostadil) appliedto each hand three times daily, resulting in a total dose of 5670 μgalprostadil applied daily.

Subjects are evaluated in the clinic prior to receiving the next studydrug regimen. If subjects tolerate the treatment regimen, subjectsproceed to the next phase of therapy. Safety is assessed by recordingthe occurrence of adverse events (AEs), as well as by changes in vitalsigns, laboratory data and physical examinations.

TABLE 4 Schedule of Assessments and Procedures Screen ReScreen Day DayDay Day Day Protocol Activity Day −21 Day −14 0 28 42 70 84 InformedConsent X Hx Physical Exam X X X X Weight and Vital Signs X X XLaboratory X X X CBC, chemistries, U/A Urine Pregnancy X DiaryInstruction X X Diary Review X  X* X X X Placebo X X InvestigationalTreatment X Concomitant Med X X X X X X SHAQ X X X SF-36 X X X AdverseEvents X X X X X X X 15-keto-PG assay+ X X Laser Doppler ColdChallenge++ X X X X *Diary review - exclude > 20% improvement in Diary+Time 0, 1, 6 hour (in selected centers) ++In selected centersStudy Compositions:

-   -   1) alprostadil topical cream, 0.33% w/w in 100 mg of cream (330        μg alprostadil).    -   2) alprostadil topical cream, 0.42% w/w in 225 mg of cream (945        μg alprostadil).    -   3) Matching Placebo Cream applied as a single application to        both hands three times daily.        Inclusion Criteria:    -   1. Males or females 18 to 70 years of age.    -   2. Active Raynaud's Phenomenon defined as episodic digital        pallor with/or without following cyanosis and/or erythema in        response to environmental cold or emotional stress.    -   3. Diagnosis of systemic sclerosis by fulfilling the preliminary        Classification Criteria of the American College of Rheumatology.    -   4. At least seven episodes of Raynaud's Phenomenon per week        during one week of patient diary.    -   5. Clinically stable disease and stable use of other Raynaud's        therapies including calcium channel blockers and Type V        phosphodiesterase inhibitors over the previous two months.    -   6. Stable immunosuppressant treatment over 3 months.    -   7. Willing and able to provide written informed consent; where        permitted, a subject's legally authorized representative may        provide written informed consent.    -   8. Negative pregnancy test within 1 week prior to dosing in        women of childbearing potential (defined as not amenorrheic        for >2 years or not surgically sterilized).    -   9. Willing and able to comply with all study procedures and        restrictions.    -   10. Adequate hand function to be able to self-administer the        study composition.        Exclusion Criteria:    -   1. Current smoker or use of nicotine products. Former smokers        must have stopped >6 months prior to study entry.    -   2. History of stroke, myocardial infarction, life-threatening        arrhythmia, uncontrolled hypertension, systemic blood        pressure<100/60, uncontrolled diabetes mellitus or unstable        angina.    -   3. Hepatic cirrhosis, active hepatitis, acute or chronic renal        insufficiency.    -   4. History of upper extremity surgical sympathectomy within the        previous six months.    -   5. Active alcoholism or drug abuse within the previous 5 years.    -   6. Pregnant or breast feeding or considering pregnancy in the        next 4 months    -   7. Past or present major psychiatric illness.    -   8. Participation in another investigational drug study within        the previous 30 days.    -   9. Use of any oral, inhaled or parenteral prostacyclins within        the previous 6 months.        Subjects excluded for any of the reasons listed above may be        re-screened for participation at any time following consultation        with the PI and Sponsor if the exclusion criteria have changed.

Outcome measures include laser Doppler imaging (LDI) of the dorsum ofhands and fingers for both placebo and test composition-treated hands.The same wavelength, scanning speed, scanning distance, DC values, andimage normalization is used for all patients. Measurements are made fromdiscrete regions of a finger and hand or average measurements of entiredigit(s). LDI data collected from discrete outlined areas on the dorsumof the finger and dorsum of hand are averaged, or a ratio between distalvs. proximal flow is calculated. Where average measurements of digit(s)are performed the mean cutaneous flow in the entire finger from the baseof the phalanx, up to and including the nailbed, is used. LDI isperformed at several time points. Baseline measurements are taken afterequilibration in room temperature, 10 minutes later, just prior to theapplication of the test composition, immediately after application oftest composition, 5 minutes and 10 minutes after application of the testcomposition; the 10 minute measurement point is immediately prior to thecold challenge, immediately after the cold challenge, and at severaltime points (5′, 10′, 15′, 20′, 30′, 1 hour, 3 hour, 6 hour) after thecold challenge.

Infrared computerized thermography is done on the both the dorsal andvolar surface of both hands immediately following LDI, takingmeasurements at the same time points listed. Proximal-distal differencesare noted. Prior studies have detected differences between the dorsum ofthe fingertips versus the dorsum of the hand in patients with Raynaud'sdisease.

Patient reports are also recorded at the time points listed above,including a visual analogue scale (VAS) pain report and sensations suchas numbness, tingling, burning, cold, pain, greasiness. When the abovepatient reports are taken, the patient's heart rate and blood pressureare also recorded.

LDI and thermography measurements are compared between the testcomposition and placebo treated fingers. Depending upon the patient'sresponse, it may be better to compare the corresponding fingersindividually rather than averaging the measurements for all the fingerson one hand compared to the average measurements of all the fingers onthe other hand. The vasospasm of Raynaud's disease can selectively occurin a subset of fingers or parts of the finger. If measurements are madeof the distal and proximal portion of the hand, then the ratio of thesevalues can be compared. Areas that respond to treatment should have aratio closer to 1, while in the typical Raynaud's disease attack, theratio would be <1. Baseline temperature changes of 2° C. or greater havebeen found to be significant in other studies.

The test composition and placebo composition are provided in identicalpackages except for identifying numbers. Two examiners/technicians whoare blinded as to package content simultaneously apply one of the studycompositions to each hand. The study compositions are applied to theentire hand, including the web spaces, with a room temperatureapplicator, without rubbing, to minimize any heat transfer.

Primary Outcome Measures:

-   -   Composite Raynaud's Index (Paper Diary)        Secondary Outcome Measures:    -   Improvement in global Quality of Life by SF-36    -   Improvement in patient function using Scleroderma Health        Assessment Questionnaire    -   Reduce the net digital ulcer burden    -   Prevent the emergence of new digital ulcers    -   Increase healing of pre-existing digital ulcers        Substudies:    -   Assay of plasma 15-keto-PG levels after initial and chronic        dosing    -   Laser Doppler velocimetry measures during controlled cold        challenge to assess effects on digital perfusion

The Intent-to-Treat (ITT) Population includes all randomized subjects.The Modified Intent-to-Treat (MITT) Population includes all randomizedsubjects who received any amount of study drug.

The disclosure of every patent, patent application, and publicationcited herein is hereby incorporated herein by reference in its entirety.

What is claimed:
 1. A method of treating Raynaud's phenomenon in asubject comprising: administering a semisolid composition comprising atotal daily dose of about 0.945 mg to about 5.7 mg a prostaglandin E₁compound to a surface of an affected body part of the subject, whereinthe subject's Raynaud's Phenomenon is secondary to systemic sclerosis,and the total daily dose is divided into 2-4 doses, and the total dailydose is administered in a regimen of separate applications over thecourse of 12-24 hours.
 2. The method of claim 1 wherein the affectedbody part is one or both hands.
 3. The method of claim 1, wherein thecomposition further comprises a skin penetration enhancer that isselected from: an N,N-di(C₁-C₈) alkylamino substituted (C₄-C₁₈) alkyl(C₂-C₁₈) carboxylic ester and pharmaceutically acceptable acid additionsalts thereof; and a (C₁-C₄)-alkyl (C₈-C₂₂) carboxylic ester.
 4. Themethod of claim 1, wherein the composition further comprises athickening agent selected from a polysaccharide gum and a chemicallymodified polysaccharide gum.
 5. The method of claim 1, wherein thecomposition is stored at room temperature.
 6. The method of claim 1wherein the composition is provided in a two-part unit dose container.